The Diploid Genome Sequence of an Individual Human

Abstract

Presented here is a genome sequence of an individual human. It was produced from ∼32 million random DNA fragments, sequenced by Sanger dideoxy technology and assembled into 4,528 scaffolds, comprising 2,810 million bases (Mb) of contiguous sequence with approximately 7.5-fold coverage for any given region. We developed a modified version of the Celera assembler to facilitate the identification and comparison of alternate alleles within this individual diploid genome. Comparison of this genome and the National Center for Biotechnology Information human reference assembly revealed more than 4.1 million DNA variants, encompassing 12.3 Mb. These variants (of which 1,288,319 were novel) included 3,213,401 single nucleotide polymorphisms (SNPs), 53,823 block substitutions (2–206 bp), 292,102 heterozygous insertion/deletion events (indels)(1–571 bp), 559,473 homozygous indels (1–82,711 bp), 90 inversions, as well as numerous segmental duplications and copy number variation regions. Non-SNP DNA variation accounts for 22% of all events identified in the donor, however they involve 74% of all variant bases. This suggests an important role for non-SNP genetic alterations in defining the diploid genome structure. Moreover, 44% of genes were heterozygous for one or more variants. Using a novel haplotype assembly strategy, we were able to span 1.5 Gb of genome sequence in segments >200 kb, providing further precision to the diploid nature of the genome. These data depict a definitive molecular portrait of a diploid human genome that provides a starting point for future genome comparisons and enables an era of individualized genomic information.

Intentions to receive individual results from whole-genome sequencing among participants in the ClinSeq study

“…Receipt of individual results from WGS, to date, has been reported primarily using case examples of scientists who have chosen to learn their own sequence. [6][7][8] At the National Institutes of Health, ClinSeq is a clinical study that aims to enroll a cohort of 41000 participants who consent to WGS and have a choice about what types of information they want returned to them. 9 This longitudinal study provides a novel opportunity for baseline assessment of preferences to learn personal health-related information from WGS.…”

The pursuit of genome-wide association studies: where are we now?

“…So far, seven human diploid genomes have been fully sequenced, and some important insights have been gained from these resequencing studies. [145][146][147][148][149][150][151] The most prominent finding from these studies is that, besides SNPs, other genetic variants are also abundant in the human genome. These studies found that in addition to the 3-4 million SNPs, several hundred-thousand of short indels (for example, sizes defined as 3 and 16 bp or less in the Bentley et al 147 and Wang et al 148 study, respectively) are also present in each individual human genome.…”

The discovery of human genetic variations and their use as disease markers: past, present and future

“…As such, the remaining several hundred thousands of indels in the range of several nucleotides to tens of nucleotides, which were identified in the recent whole genome resequencing experiments, do not currently have their own category. [27][28][29][30][31][32][33] For example, Wang et al (2008) 29 found B140 000 indels within 1-3 bp in the Han Chinese YH genome, and B400 000 indels defined from 1 to 16 bp were also detected in the African NA18507 genome by Bentley et al (2008). 30 Perhaps a new category such as 'short indels' needs to be created to fit them in, and those indels between 100 bp to 1 kb should probably be renamed as 'intermediate indels' (Figures 1c and d).…”